This invention relates to certain 2-substituted thio-6-substituted-carbapen-2-em-3-carboxylic acids (I) and their pharmaceutically acceptable salt, ester and amide derivatives which are useful as antibiotics: ##STR3## wherein: R.sup.7 and R.sup.8 are independently selected from the group consisting of hydrogen, substituted and unsubstituted: alkyl having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl such as phenyl; aralkyl, wherein the aryl moiety is phenyl and the alkyl chain has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: amino, mono-, di- and trialkylamino, amido, hydroxyl, alkoxyl, acyloxy, sulfamoyl, ureido, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen or nitrogen atoms; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms.
R.sup.5 is, inter alia, cyano; substituted and unsubstituted: acyl such as ##STR4## (R is substituted or unsubstituted: phenyl or alkyl having from 1-10 carbon atoms); PA0 R.sup.6 is, inter alia, hydrogen; R.sup.5 ; substituted or unsubstituted: alkyl having from 1-10 carbon atoms; aryl, such as phenyl; and heteroaryl, such as furyl, but in general having from 4-6 atoms in the ring wherein the hetero atom or atoms are selected from oxygen, or nitrogen. Relative to the above definitions of R.sup.5 and R.sup.6 the substituent or substituents thereon may be selected from the group consisting of bromo, chloro, fluoro, nitro, cyano, alkoxycarbonyl having from 2-7 carbon atoms, alkoxyl having from 1-6 carbon atoms, phenyloxy, dialkylamino, and alkylarylamino wherein relative to the last two mentioned substituents the alkyl moiety has from 1-6 carbon atoms and the aryl moiety has from 1-6 carbon atoms and the aryl moiety is phenyl. The groups R.sup.7, R.sup.8, R.sup.5 and R.sup.6 are additionally defined below. PA0 1. U.S. Pat. No. 3,950,357; PA0 2. U.S. Pat. No. 4,234,596; PA0 3. EPO Publication No. 0001628 Application No. 78101157.2. PA0 CHO PA0 --CO.phi. (.phi.=phenyl) PA0 --CO.sub.2 Et (Et=ethyl) PA0 --CO.sub.2 CH.sub.2 .phi. ##STR8##
This invention also relates to the carboxyl derivatives of I which are antibiotics and which may be represented by the following generic structure (I): ##STR5## wherein X' is oxygen, sulphur or NR' (R'=H or lower alkyl having 1-6 carbon atoms); and R.sup.3' is, inter alia, representatively selected from the group consisting of hydrogen, conventional blocking groups such as trialkylsilyl, acyl and the pharmaceutically acceptable salt, ester and amide moieties known in the bicyclic .beta.-lactam antibiotic art; the definition of R.sup.3' is given in greater detail below.
This invention also relates to processes for the preparation of such compounds (I); pharmaceutical compositions comprising such compounds; and to methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
There is a continuing need for new antibiotics. For unfortunately, there is no static effectiveness of any given antibiotic because continued wide scale usage selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues.
Thus, it is an object of the present invention to provide a novel class of antibiotics which are useful in animal and human therapy and in inanimate systems. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. aureus, Strep. pyogenes and B. subtilis, and gram negative bacteria such as E. coli, Pseudomonas, Proteus morganii, Serratia, and Klebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salts and esters; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.